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Mutations of the Amyloid Precursor Protein, from which the amyloid β peptide Aβ42 is cleaved, are associated with familial Alzheimer's disease. The disease-relevant familial mutations include the Arctic (E22G), Iowa (D23N), Italian (E22K), Dutch (E22Q), Japanese (D7N), English (D6R), and Flemish (A21G) variants. A detailed mechanistic understanding of the aggregation behavior of the mutant peptides at the residue level is, however, still lacking. We report here a study of the aggregation kinetics of these mutants in vitro by pulsed hydrogen-deuterium exchange mass spectrometry (HDX-MS) to obtain a temporally and sequence resolved picture of their self-assembly. For all variants, HDX occurs to give a bimodal distribution representing two soluble classes of aggregates, one protected and one solvent-exposed. There is no evidence of other classes of structural intermediates within the detection limits of the HDX approach. The fractional changes in the bimodal exchange profiles for several regions of Aβ42 reveal that the central and C-terminal peptides gain protection upon fibril formation, whereas the N-terminal regions remain largely solvent-accessible. For these mutants, all peptide fragments follow the same kinetics, acquiring solvent protection at the same time, further supporting that there are no significant populations of intermediate species under our experimental conditions. The results demonstrate the potential of pulsed HDX-MS for resolving the region-specific aggregation behavior of Aβ42 isoforms in solution where X-ray crystallography and solid-state NMR (ssNMR) are challenged.
Illes‐Toth et al. (Fri,) studied this question.